tbuckley/cabot-search huggingface dataset:
NIMG-08. AN INTEGRATED INFORMATICS MODEL COMBINING CLINICAL FACTORS, RADIOMICS AND A NOVEL CONNECTOMICS FRAMEWORK TO DISTINGUISH PATHOLOGICALLY-PROVEN RADIONECROSIS FROM PROGRESSION IN TREATED BRAIN METASTASES
Authors: Emerson Lee, Linda Cao, Parekh Vishwa, Scott Chen, Kristin Redmond, Luke Peng, Jacobs Michael, Lawrence Kleinberg
Journal: Neuro-Oncology (2022)

Abstract PURPOSE/OBJECTIVE(S) To distinguish radionecrosis (RN) from true progression (TP) in brain metastases treated with stereotactic radiosurgery (SRS), we apply machine learning to create a multi-domain model that incorporates clinical factors, multiparametric radiomics(mpRads), and tumor connectomics, a novel MRI-based complex graph theory framework that describes the intricate network of relationships within the tumor and surrounding tissue. MATERIALS/METHODS Metastases treated with SRS that had pathologic confirmation of RN vs. TP after imaging progression were included from a single institution. Regions of interest were manually segmented using the single largest diameter of the T1 post-contrast(T1C) lesion plus the corresponding area of T2 FLAIR hyperintensity. We developed an Integrated Radiomics Informatics System (IRIS) based on an isomap support vector machine (IsoSVM) model to classify TP from RN using leave-one-out cross-validation (LOOCV). Class imbalance was resolved using differential misclassification weighting during model training using IRIS. Area under the receiver operating characteristic (AUC-ROC) and AUC-PR (precision recall) analysis were performed. RESULTS We analyzed 135 lesions in 110 patients. There were 43 cases (31.9%) of RN and 92 cases (68.1%) of TP. The top-performing connectomics features were degree centrality (increased with RN) and average path length (decreased with RN), suggesting greater “connectivity” and increased similarity in intralesional features between the T1C and FLAIR signal regions in RN cases. The top-performing radiomics feature was multidimensional entropy (increased in TP), demonstrating greater heterogeneity in TP cases. Finally, the top-performing clinical features were prior RT before SRS, histology, and treated lesion size. The LOOCV IsoSVM model successfully classified TP from RN with an AUC-ROC of 0.84 (95% CI: 0.77-0.90) and AUC-PR of 0.90 (95% CI: 0.82-0.95). The F1 score was 0.89. CONCLUSION Our novel machine-learning framework was able to efficiently combine features from multiple domains (i.e., radiomics, connectomics, and clinical factors) to distinguish pathologically-proven TP from RN with excellent discrimination.
SURG-36. EVALUATION OF SURGICAL RESULTS AND PREDICTIVE FACTORS OF HYDROCEPHALUS IN PEDIATRIC PATIENTS WITH POSTERIOR FOSSA TUMORS
Authors: Cleiton Formentin, Leo Gordiano Matias, Lucas Souza Rodrigues de Santos Santos, Andrei Fernandes Joaquim, Helder Tedeschi, Enrico Ghizoni
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Infratentorial tumors represent 45 to 60% of all brain tumors in children and are associated with hydrocephalus in 70 to 90% of cases. The aim of this study is to describe and analyze the surgical results and correlate them with the incidence of hydrocephalus, as well as identify predictive factors of hydrocephalus in pediatric patients underwent to a surgical treatment of posterior fossa tumors. METHODS This is a retrospective observational study, based on demographic, clinical and radiological information of pediatric patients underwent to surgical resection of posterior fossa tumors by a single group between 2011 and 2019. RESULTS We included 135 patients with a mean age of 7.56 years, mean follow-up of 35.7 months and overall survival of 18.8 months. Considering the histology, most tumors were pilocytic astrocytomas (34.1%), followed by medulloblastomas (27.4%) Total resection was achieved in 77.8% and tumor recurrence was observed in 16.2%. The rate of hydrocephalus was 36.3%, with most shunt procedures performed preoperatively. There was a high rate of complications associated with shunting (42.9%), mostly represented by infection (71.5%). Patients with hydrocephalus were younger (p = 0.001), showing a faster evolution between the onset of symptoms and diagnosis (p = 0.008). Tumor volume (p = 0.1) and location (p = 0.32) were not statistically significant for hydrocephalus, however, the presence of leptomeningeal disease (p = 0.001) was. The resection rate was also significant, with lesions totally resected showing the best results (p = 0.009). Regarding tumor histology, 33.3% of patients with medulloblastoma and 62.5% of patients with ependymoma were shunted. CONCLUSION One third of children with posterior fossa tumors will require a shunt procedure. Some factors should guide the neurosurgeon during patient counseling and surgical planning to minimize the use of permanent shunts and avoid related complications.
CTNI-51. FEASIBILITY AND SAFETY OF NEUROSURGICAL RESECTION AND INTRA-OPERATIVE RADIATION THERAPY USING THE XOFT AXXENT ELECTRONIC BRACHYTHERAPY SYSTEM AND BEVACIZUMAB IN RECURRENT GLIOBLASTOMA
Authors: Naveed Wagle, Garni Barkhoudarian, Lisa Chaiken, Robert Wollman, Akanksha Sharma, Jose Carrillo, Minh Nguyen, Judy Truong, Jared Chow, Emma Chacon, Santosh Kesari
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor. External beam radiation therapy (EBRT) is widely recognized as an effective treatment for primary GBM. EBRT applied after GBM resection is associated with an increase in overall survival. Beyond upfront therapy with radiation and temozolomide chemotherapy, there is no standard therapy that has been proven effective. Re-irradiation with ERBT is minimally effective and with significant comorbidities. Our study uses IORT at the time of re-resection in patients who have recurrent, operable GBM after failure of who received primary EBRT and temozolamide in their first course of treatment. IORT allows the delivery of a large effective radiation dose applied directly to the tumor bed at the time of resection. This affords direct radiation to be delivered to the micro- and macroscopic tumor remnants in the vicinity of the resection cavity immediately following gross resection. In contrast, the more distant, surrounding brain tissue does not receive high radiation exposure. This Phase II study continues to accrue subjects with the primary endpoint of overall survival and several secondary endpoints that includes progression free survival, quality of life, and adverse events/safety. To date, five patients have been treated on this protocol. The technical feasibility and safety of administering intraoperative radiation with the Xoft System has been established in this cohort. Preliminary GLIOX Trial findings demonstrate the safety and feasibility of using the Xoft Axxent® Electronic Brachytherapy System to administer intracranial radiation during resection of recurrent glioblastomas. We will report new and expansive study results to include these early findings.
CTNI-20. RESULTS OF A PHASE 1/2 CLINICAL TRIAL OF BLOOD-BRAIN BARRIER (BBB) OPENING WITH THE SONOCLOUD-9 IMPLANTABLE ULTRASOUND DEVICE IN RECURRENT GLIOBLASTOMA PATIENTS RECEIVING IV CARBOPLATIN
Authors: Alexandre Carpentier, Adam M Sonabend, Roger Stupp, Olivier Chinot, Henry Dufour, François Ducray, Philippe Menei, John de Groot, Jeffrey Weinberg, Carole Desseaux, Michael Canney, Ahmed Idbaih
Journal: Neuro-Oncology (2022)

Abstract Low intensity pulsed ultrasound in combination with microbubbles can be used to temporarily disrupt the blood-brain barrier (BBB). A phase 1/2 clinical study (NCT03744026) was initiated to demonstrate the safety and efficacy of BBB disruption using an implantable ultrasound system (SonoCloud-9) in patients with recurrent glioblastoma receiving carboplatin chemotherapy. The SonoCloud-9 device, which contains nine, 1-MHz, 10-mm diameter ultrasound emitters (Carthera, Paris, France) was placed at the end of tumor resection and replaced the bone flap. The device was activated 9-14 days after surgery for a duration of 270 seconds every four weeks until progression or treatment completion, concomitantly with IV DEFINITY microbubbles (10 ml/kg, Lantheus, Billerica, US). The Phase 1 cohort consisted of an escalation of BBB disruption volume by activation of 3 (n = 3), 6 (n = 3), then 9 (n = 3) emitters of the device. Dose limiting toxicity (DLT) was assessed during the first two weeks after the 1st sonication. A subsequent expansion cohort consisted of patients treated with nine emitters in which the primary endpoint was assessment of BBB opening on MRI using gadolinium (&amp;lt; 1 hr after sonication). All patients received carboplatin either after (n = 21) or before (n = 12) device activation to disrupt the BBB. In addition, a sub-study was performed to investigate carboplatin concentration enhancement in the peritumoral region with sonication at time of device implantation. Study accrual is complete with 33 patients having been implanted and received at least one sonication. A total of 101 sonications were performed (range = 1-10 sonication sessions/patient). No DLTs were observed. Five serious adverse events (all resolved) were considered as possibly related to the study procedure. BBB disruption was confirmed by gadolinium enhancement after sonication. In three patients who underwent intraoperative sonication and carboplatin administration, a 7.58-fold increase in brain/plasma drug levels was demonstrated. Updated survival results will be presented.
BIOM-23. MOLECULAR MARKER TESTING AND REPORTING COMPLETENESS FOR ADULT-TYPE DIFFUSE GLIOMAS IN THE UNITED STATES
Authors: Corey Neff, Gino Cioffi, Kristin Waite, Carol Kruchko, Jill Barnholtz-Sloan, Quinn Ostrom, Bryan Iorgulescu
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND A newly developed brain molecular marker (BMM) data item was implemented by U.S. cancer registries for individuals diagnosed with brain tumors in 2018—including IDH and 1p/19q-codeletion statuses for adult-type diffuse gliomas. We thus investigated the testing/reporting completeness of BMM in the U.S. METHODS Cases of histopathologically-confirmed glioblastoma, astrocytoma, and oligodendroglioma diagnosed in 2018 were identified in the National Cancer Database. Adjusted odds ratios (ORadj) and 95% confidence intervals (95CI) of BMM testing/reporting were evaluated for association with selected patient, treatment, and facility-level characteristics using multivariable logistic regression. As a secondary analysis, predictors of MGMT promoter methylation testing/reporting among IDH-wildtype glioblastoma individuals was assessed. RESULTS Among 7,370 histopathologically-diagnosed adult-type diffuse gliomas nationally, the overall BMM testing/reporting completeness was 81%. Compared to biopsy-only cases, the odds of testing/reporting increased for increased for subtotal (ORadj= 1.38 [95CI: 1.19-1.61], p&amp;lt; 0.001) and gross total resection (ORadj=1.53 [95CI: 1.33-1.77], p&amp;lt; 0.001). Furthermore, the odds of testing/reporting completeness were lowest at community centers (hospitals (65.8%; ORadj=0.33 [95CI: 0.24-0.44], p&amp;lt; 0.001) and highest at academic/NCI-designated comprehensive cancer centers (85.3%; referent). By geographical location, BMM testing/reporting completeness ranged from a high of 86.9% at New England (referent) to a low of 75.2% in the West South Central region (ORadj=0.55 [95CI: 0.39-0.76]; p&amp;lt; 0.001). Extent of resection, facility type, and facility location were additionally significant predictors of MGMT testing/reporting among IDH-wildtype glioblastoma cases. CONCLUSION Initial BMM testing/reporting completeness for individuals with adult-type diffuse gliomas in the U.S. were favorable, although patterns varied by hospital attributes and extent of resection.
STEM-27. MECHANOSENSITIVE BRAIN TUMOR CELLS CONSTRUCT BLOOD-TUMOR BARRIER TO MASK CHEMOSENSITIVITY
Authors: Xin Chen, Ali Momin, Siyi Wanggou, Xian Wang, Weifan Dong, Jerry Fan, Yu Sun, Xuejun Li, Xi Huang
Journal: Neuro-Oncology (2022)

Abstract Two major obstacles in brain cancer treatment are the blood-tumor barrier (BTB) and quiescent tumor cells. Here we show that Sox2+ tumor cells directly project cellular processes to ensheathe capillaries in medulloblastoma (MB), a process that depends on the mechanosensitive ion channel Piezo2. MB develops a tissue stiffness gradient as a function of distance to capillaries. Sox2+ tumor cells perceive substrate stiffness to sustain local intracellular calcium, actomyosin tension, and adhesion to promote cellular process growth and cell surface sequestration of β-Catenin. Piezo2 knockout reverses WNT/β-Catenin signaling states between Sox2+ tumor cells and endothelial cells, compromises the BTB, reduces the quiescence of Sox2+ tumor cells, and markedly enhances MB response to chemotherapy. Our study reveals that mechanosensitive tumor cells construct the BTB to mask tumor chemosensitivity. Targeting Piezo2 addresses the BTB and tumor quiescence properties that underlie therapy failures in brain cancer.
RTID-06. A RANDOMIZED CONTROLLED TRIAL USING ACCELERATOR-BASED BNCT SYSTEM FOR REFRACTORY RECURRENT HIGH-GRADE MENINGIOMA
Authors: Shin-Ichi Miyatake, Masahiko Wanibuchi, Shinji Kawabata, Motomasa Furuse, Koji Ono, Keiji Nihei, Kazuhiko Akita, Naonori Ko
Journal: Neuro-Oncology (2022)

Abstract BACKGROUNDS Recently, nuclear reactors have been replaced with accelerator-based neutron sources (ABNS) for boron neutron capture therapy (BNCT). High-grade meningiomas (HGM) are refractory, especially recurred after some radiotherapy. We are now applying randomized controlled trial (RCT) of “A phase II clinical trial using accelerator-based BNCT system for refractory recurrent high-grade meningioma”. STUDY DESIGN PMDA in Japan which is a counter part of FDA in USA suggested the importance of RCT even for this exploratory clinical trial for HGM. Along to this suggestion, we prepared 2 study groups, BNCT test treatment group and control best supportive care (BSC) group. Progression free survival (PFS) was set-up as primary endpoint. Rescue BNCT is allowed for control group patients, if they showed progress disease (PD) during observation. Two-dimensional modified Macdonald criteria is adopted for assessment. METHODS The trial started in August 2019. Eighteen subjects were enrolled and divided in 12 and 6 subjects for BNCT and control BSC group, respectively. Cyclotron-based ABNS system was used for neutron source. Neutron-irradiation time is determined not to exceed to 7.5 Gy-Eq for scalp dose which was referencing preceding phase I trial for malignant gliomas. The last patient-in was August 2021. INTERIM RESULTS (as of April 30, 2022): All 6 cases of control group were judges as PD. Seven out of 11 cases of BNCT group were judged as PD. One case of BNCT group dropped out from the study with withdrawal of consent. Median PFS were 8 and 64 weeks for control group and BNCT group, respectively. Log-rank test showed marked statistical difference with p-value of 0.000401 between these 2 groups. CONCLUSIONS This RCT showed a marked difference of PFS between accelerator-based BNCT group and control group, so far. We will keep on observation at least next 2 years for other endpoints.
TMET-02. THERAPEUTIC EFFICACY OF A NOVEL BRAIN PENETRANT SCD INHIBITOR ON BREAST CANCER BRAIN METASTASES
Authors: Alessandro Sammarco, Katharina Eyme, Roshani Jha, Willian Das Neves Silva, Rudolph Neustadt, Ian Ford, Steven J Bensinger, Valentina Zappulli, Xandra Breakefield, Christian E Badr
Journal: Neuro-Oncology (2022)

Abstract Brain metastases are a significant therapeutic challenge and are associated with high morbidity and mortality. Recent evidence suggests that brain metastases have increased fatty acid synthesis compared to extracranial tumors. The enzyme stearoyl-CoA desaturase (SCD), which converts saturated long-chain fatty acids into monounsaturated fatty acids, is often upregulated in breast cancer brain metastasis (BCBM) and is considered a promising therapeutic target. However, the lack of brain penetrant SCD inhibitors limited their use in patients. This study aimed to investigate the therapeutic efficacy of a clinical-stage brain penetrant inhibitor of SCD to treat BCBM. We found that pharmacologic inhibition of SCD in multiple breast cancer cell lines induced significant cytotoxicity, mainly by apoptosis. Gas chromatography/mass spectrometry confirmed that the fatty acid desaturation index, which measures SCD activity, was significantly lower after treatment. SCD inhibition triggered endoplasmic reticulum (ER) stress and increased DNA damage due to a higher production of reactive oxygen species. Further, SCD inhibition decreased DNA damage repair by inhibiting homology-directed repair in vitro and in a mouse model of breast cancer. Notably, inhibition of SCD led to a significant decrease in tumor growth in a subcutaneous mouse model of breast cancer and a significant increase in overall survival in a BCBM mouse model. Cytotoxicity was enhanced when this SCD inhibitor was combined with either a DNA damage-inducing agent (temozolomide or radiation) or with a PARP inhibitor (Niraparib). Finally, we observed that combination therapy of SCD inhibition and Niraparib significantly increased overall survival in a BCBM mouse model. Our results suggest that inhibition of SCD alone or in combination with a PARP inhibitor is a promising therapeutic strategy to treat BCBM.
BIOM-04. CORRELATIVE PERFORMANCE OF CEREBROSPINAL FLUID (CSF) CIRCULATING TUMOR CELLS (CTC) AND CELL-FREE TUMOR-DERIVED DNA (CTDNA) IN LEPTOMENINGEAL METASTASES (LM) AND PARENCHYMAL BRAIN METASTASES (BM)
Authors: Maria Diaz, Anne Reiner, Claudia Huereca, Robert Young, Maria Arcila, Marc Rosenblum, Lakshmi Ramanathan, Tejus Bale, Elena Pentsova
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND CSF-CTC analysis through the CellSearch® platform has been studied as a diagnostic and prognostic tool for LM from solid tumors. CSF-ctDNA can be detected in LM and/or BM, with unclear significance. We aimed to evaluate CSF-CTCs and CSF-ctDNA as predictors of LM diagnosis and survival in LM and BM. METHODS We retrospectively reviewed charts of patients with solid tumors who underwent CSF-CTC and ctDNA evaluation from the same lumbar puncture between 2016-2021 at Memorial Sloan Kettering Cancer Center. LM was diagnosed by MRI and/or CSF cytology; CSF-ctDNA was considered “positive” if next-generation sequencing (NGS) detected ≥ 1 mutations using clinically validated thresholds. Associations with newly diagnosed LM were performed using logistic regression, and with development of LM using cause-specific competing risks models. Survival analyses were performed using Cox proportional hazards modeling from date of first CSF collection, and adjusted by LM as a time-dependent variable. RESULTS Out of 151 total patients, 99 had LM at the time of CSF analysis (58/99 with newly diagnosed LM, within 30 days of first CSF collection), and 52 had BM only, of which 8/52 (15%) developed LM later (median time from CSF to LM=235 days, range 57-364). CSF-CTCs and CSF-ctDNA were predictive of newly diagnosed LM (OR=1.006, 95% CI:1.002-1.01, p=0.002 for continuous CSF-CTCs; OR=3.60, 95% CI:1.65-7.87, p=0.001 for positive CSF-ctDNA). In a small cohort of patients without LM, CSF-ctDNA was almost statistically significant in predicting later development of LM (HR=4.14, 95% CI: 0.98-17.57, p=0.054) while continuous CSF-CTCs were not (HR=1.02, 95% CI: 0.99-1.04, p=0.21). In all patients, both CSF-CTCs (OR=1.004, 95% CI: 1.001-1.006, p=0.002) and CSF-ctDNA (OR=2.49, 95% CI: 1.51-4.15, p=0.0004) predicted survival. CONCLUSION CSF-ctDNA could predict development of LM in patients with BM. Presence of CTCs and ctDNA in CSF were associated with poor survival in patients with central nervous system metastases.
QLTI-04. USING VARIANT ALLELIC FRACTION OF DRIVER MUTATIONS IN ADULT-TYPE DIFFUSE GLIOMA TO IMPROVE MGMT PROMOTER METHYLATION TESTING
Authors: Matthew McCord, Kristyn Galbraith, Pouya Jamshidi, Rimas Lukas, Hui Zhang, Lawrence Jennings, Matija Snuderl, Craig Horbinski
Journal: Neuro-Oncology (2022)

Abstract Methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter predicts favorable response to temozolomide in adult-type diffuse gliomas. Accurate MGMT results require adequate tumor cellularity. Too many admixed non-neoplastic cells (which are always MGMT unmethylated) may cause false-negative results. Currently, ~70% tumor cellularity, based on estimation by microscopy, is recommended for reliable testing. However, this is subjective, and few cases are actually excluded from testing, so there is a risk of false-negative MGMT results. Since adult-type diffuse gliomas usually have heterozygous driver mutations in nearly all tumor cells, including IDH1, IDH2, and/or TERT, we determined whether the variant allelic fraction (VAF) of these mutations could serve as a better quality control metric in MGMT assays. A discovery cohort consisted of 175 gliomas (112 IDH-wildtype, TERT-mutant GBMs, 34 IDH-mutant astrocytomas, and 29 oligodendrogliomas). A validation cohort consisted of 50 gliomas (32 GBMs, 11 IDH-mutant astrocytomas, 7 oligodendrogliomas); all cases had MGMT pyrosequencing and NGS data. Gliomas with average ≥ 10% methylation of 4 measured CpG sites on the MGMT promoter were considered positive, as per standard cutoffs. The discovery cohort showed positive correlation between VAF and MGMT methylation among all gliomas (slope=0.26, R2=0.034, P=0.014). The largest drop-off in MGMT methylation occurred with VAF &amp;lt; 13% (average MGMT of 4.77% versus 18.65% for VAF ≥ 13%, P=0.037). Among GBMs, only 1/7 (14.0%) with TERT VAF &amp;lt; 13% met the cutoff for MGMT promoter methylation, versus 39/105 (37.0%) with VAF ≥ 13%. Based on our previous study (PMID 33830235), approximately 36.5% of GBMs should be positive. The validation cohort showed a similar pattern, wherein gliomas with driver mutation VAF &amp;lt; 13% had average MGMT of 5.75% versus 14.94% for VAF ≥ 13%. In summary, our results suggest that glioma samples with driver mutation VAF below 13% are at higher risk of false-negative MGMT promoter methylation.